EP0441349A1 - Pyrroloazepine derivatives - Google Patents
Pyrroloazepine derivatives Download PDFInfo
- Publication number
- EP0441349A1 EP0441349A1 EP91101616A EP91101616A EP0441349A1 EP 0441349 A1 EP0441349 A1 EP 0441349A1 EP 91101616 A EP91101616 A EP 91101616A EP 91101616 A EP91101616 A EP 91101616A EP 0441349 A1 EP0441349 A1 EP 0441349A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- group
- compound
- following formula
- hydrogen atom
- substituted
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 0 CC1(*)CCN(C)CC1 Chemical compound CC1(*)CCN(C)CC1 0.000 description 3
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Definitions
- the present invention relates to novel pyrroloazepine derivatives, and more specifically to novel pyrroloazepine derivatives and salts thereof, said derivatives and salts having strong anti-a i action and anti-serotonin action but low toxicity and being useful as therapeutics for circulatory diseases such as hypertension and congestive heart failure, their preparation processes thereof and therapeutics for circulatory diseases, said therapeutics containing them as active ingredients.
- ⁇ 1 -blockers represented by prazosin have such merits that (1) their antihypertensive action is strong and sure, (2) they do not give adverse influence to the lipidometabolic and glycometabolic systems and (3) they can be easily used for hypertensives having complication. Their development is hence actively under way. Clinically-applied examples of such ⁇ 1 -blockers include bunazosin, doxazosin, terazosin and urapidil in addition to prazosin.
- ⁇ 1 -Blockers are however accompanied by the drawback that they generally have side effects such as orthostatic disorder and reflex tachycardia, tend to induce orthostatic hypotension especially when administered to aged people and hence require attention.
- ketanserin having both anti-serotonin action and anti-ai action has been developed as a drug effective for senile hypertension and the like.
- this ketanserin may not be able to exhibit, for example, sufficient hypotensive action in some instances, and its side effects to the central nervous system such as drowsiness and sedative action have posed problems.
- the present inventors synthesized numerous compounds and investigated their pharmacological effects with a view toward obtaining drugs having both anti-serotonin action and anti-a i action, strong hypertensive action, and low side effects and toxicity.
- This invention therefore provides a pyrroloazepine derivative represented by the following formula (I): wherein R means a hydrogen atom, a linear or branched C 1-6 alkyl group or a C 7-10 aralkyl group, A denotes a linear or branched C 2-10 alkylene, alkenylene or alkynylene group, Z stands for O, NOR, in which R, is a hydrogen atom or an alkyl, aryl or aralkyl group, or NOCOR s in which R s is a hydrogen atom or an alkyl, aryl or aralkyl group, and Y means a group in which R 2 means a hydrogen atom or a cyano group, R 3 an Rs' may be the same or different and individually denote a substituted or unsubstituted phenyl group or a substituted or unsubstituted aralkyl group, and B is an oxygen or sulfur atom or a carbonyl, substituted or
- the pyrroloazepine derivatives (I) and their pharmacologically acceptable salts according to the present invention are drugs having anti-ai action and anti-serotonin action and have a high degree of safety. They can therefore be used, for example, as novel therapeutics for circulatory diseases.
- Preferred examples of group R include hydrogen atom, and methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and benzyl groups.
- R 3 and Rs' include a phenyl group; a phenyl group substituted by one or more halogen atoms such as fluorine, chlorine and bromine, and C 1-4 alkoxy groups such as methoxy and ethoxy groups; a benzyl group; and a diphenylmethyl group.
- R 3 and Rs' mean substituted aralkyl groups, each substituent may be bonded to either the aryl moiety or the alkyl moiety.
- exemplary substituents include lower alkyl groups such as methyl, ethyl and propyl; a phenyl group; and a phenyl group substituted by one or more halogen atoms such as fluorine, chlorine and bromine and C 1 - 4 alkoxy groups such as methoxy and ethoxy groups.
- groups of the substituted or unsubstituted, cyclic or acyclic acetal represented by B include and
- preferred examples of group R 1 include hydrogen atom, lower alkyl groups such as methyl group, and C 7-10 aralkyl groups such as benzyl group.
- Preferred examples of Rs include lower alkyl groups such as methyl groups and aryl groups such as phenyl group.
- the pyrroloazepine derivatives (I) according to the present invention can be prepared by a desired conventional method. However, the pyrroloazepine derivatives (I) are preferably prepared, for example, by any of the following processes:
- the conversion from the compound (II) to the compound (III) is effected by causing the compound represented by formula (V) to act on the compound (II) in the presence of an organic or inorganic base.
- substituents which is easily replaceable with an amino group, as group X in the compound (V) include halogen atoms such as chlorine and bromine atoms, methanesulfonyl group and p-toluenesulfonyl group.
- Any solvent can be used in this reaction as long as it does not take part in the reaction.
- Illustrative solvents include dimethylformamide, acetonitrile, dimethylsulfoxide, tetrahydrofuran, dioxane and acetone.
- exemplary organic or inorganic bases include triethylamine, pyridine, collidine, 1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU) sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium ethoxide, and potassium t-butoxide.
- DBU 1,8-diazabicyclo[5.4.0]-undec-7-ene
- the reaction is conducted at -20 C to the reflux temperature.
- the compound (la) by reacting the compound (III) with the nitrogen-containing cyclic compound (IV), it is only necessary to react at room temperature to 150°C the nitrogen-containing cyclic compound (IV) or an organic acid or inorganic acid salt thereof with the compound (III), optionally together with an organic base such as triethylamine, pyridine, collidine, DBU or potassium t-butoxide or an inorganic base such as potassium carbonate, sodium carbonate, potassium hydroxide or sodium hydroxide, optionally after adding an iodide such as sodium iodide or potassium iodide.
- an organic base such as triethylamine, pyridine, collidine, DBU or potassium t-butoxide
- an inorganic base such as potassium carbonate, sodium carbonate, potassium hydroxide or sodium hydroxide
- nitrogen-containing cyclic compound (IV) examples include 4-phenylpiperidine, 4-benzylpiperidine, 4-[bis(4-fluorophenyl)methylene]piperidine, ⁇ , ⁇ -bis-4-(fluorophenyl)-4-piperidinemethanol, 4-(diphenylmethoxy)piperidine, 4-cyano-4-phenylpiperidine, 4-4-(fluorobenzoyl)piperidine, 4-benzoylpiperidine, 4-(4-methoxybenzoyl)piperidine, 4-(4-chlorobenzoyl)piperidine, 3-(4-fluorobenzoyl)piperidine, 3-benzoylpyrrolidine, 3-(4-fluorobenzoyl)pyrrolidine, 4-(4-fluorophenoxy)piperidine, 4-[(4-fluorophenyl)thio]piperidine, 4-[-(4-fluorophenyl)-sulfinyl]piperidine, 4-[
- novel compounds can each be prepared in accordance with the following reaction scheme, namely, by reacting a pyrrole-2-carboxylic acid represented by the formula (VI) or a derivative thereof with a ,8-amino acid represented by the formula (VII) or a derivative thereof or an organic or inorganic salt of the p-amino acid or the derivative thereof and optionally removing the protecting group, thereby obtaining the compound represented by the formula (VIII) and then ring-closing this compound.
- R has the same meaning as defined above
- R 4 means a hydrogen atom or a carboxyl-protecting group
- W denotes a hydroxyl group or a substituent easily replaceable with an amino group.
- Examples of the substituent easily replaceable with an amino group as represented by W in the compound (VI) include halogen atoms, carboxylic acid residue and the like.
- the carboxyl-protecting group it is possible to use, in addition to lower alkyl groups such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl and t-butyl and C 7-20 aralkyl groups such as benzyl and 9-anthrylmethyl, the conventional protecting groups described by T.W. Greene in "Protective Group in Organic Synthesis” (John Wiley & Sons, Inc.) and the like.
- Each compound (VIII) thus obtained is subjected to a cyclizing reaction, optionally after removing the protecting group by virtue of a suitable method such as the action of an acid or a base, or catalytic reduction.
- This cyclizing reaction is conducted by treating the compound (VIII) together with an organic acid such as methanesulfonic acid, an inorganic acid such as sulfuric acid or polyphosphoric acid or a mixture of such an organic or inorganic acid and diphosphorus pentoxide at room temperature to 170° C, preferably at 80-120 * C.
- an organic acid such as methanesulfonic acid, an inorganic acid such as sulfuric acid or polyphosphoric acid or a mixture of such an organic or inorganic acid and diphosphorus pentoxide
- a solvent which does not take part in the reaction may be added as needed.
- the cyclizing reaction can also be practiced by treating the compound (VIII) with oxalyl chloride, thionyl chloride, thionyl bromide, oxalyl bromide, phosgene, phosphorus trichloride, phosphorus tribromide, phosphoryl chloride, phosphoryl bromide or the like, optionally in the presence of a catalyst to convert the compound (VIII) to its corresponding acid halide and then treating the acid halide at -20 C to reflux temperature in the presence of a Lewis acid such as aluminum chloride, aluminum bromide, boron trifluorideether complex or tin tetrachloride in a solvent such as dichloromethane, 1,2-dichloroethane or nitromethane or heating the acid halide in acetic acid.
- a Lewis acid such as aluminum chloride, aluminum bromide, boron trifluorideether complex or tin tetrachloride in a solvent
- the compounds (II) obtained in the above manner can be used directly as starting materials for the preparation of the compounds (la) of the present invention. They can also be used after purification by a conventional purification method, for example, by recrystallization or column chromatography if necessary.
- the compounds (Ib) in which Z is represented by NOR 1 can each be prepared in accordance with the following reaction formula, namely, (i) by causing a hydroxyamine represented by the formula (IX) or a derivative thereof or a salt of the hydroxylamine or the derivative to act on the compound (la) obtained by the above-described reaction or (ii) by causing the hydroxylamine or its derivative (IX) or a salt of the hydroxylamine or the derivative to act on the compound (III) and then causing a nitrogen-containing cyclic compound (IV) or a salt thereof to act further.
- A, R, Ri, X and Y have the same meanings as defined above.
- the reaction between the compound (la) or (III) and the hydroxylamine or its derivative (IX) is practiced, if necessary, in the presence of an organic base such as pyridine, triethylamine, collidine, DBU or sodium acetate or an inorganic base such as potassium carbonate or sodium hydroxide.
- an organic base such as pyridine, triethylamine, collidine, DBU or sodium acetate or an inorganic base such as potassium carbonate or sodium hydroxide.
- the hydroxylamine or its derivative (IX) may also be used in the form of an organic acid salt or an inorganic acid salt.
- the compound (X) obtained by the reaction of the compound (III) with the compound (IX) can be reacted further with the nitrogen-containing cyclic compound (IV) by the method described above, whereby the compound (X) can be converted to the compound (Ib).
- the hydroxylamine or its derivative (IX) Upon preparation of the compound (Ib), it is determined depending on the structure and properties of the nitrogen-containing cyclic compound (IV) whether the hydroxylamine or its derivative (IX) should be reacted to the compound (III) or to the compound (la). Where there is a group reactive to the hydroxylamine or its derivative (IX), such as a carbonyl group, in the nitrogen-containing cyclic compound (IV), it is desirable to choose the process that the hydroxylamine or its derivative (IX) is reacted to the compound (III).
- a group reactive to the hydroxylamine or its derivative (IX) such as a carbonyl group
- the compounds (Ic) in which X is represented by can each be prepared (i) by acylating the compound (Ib') [i.e., the compound of formula (Ib) in which R 1 is H)], which has been obtained by the above reaction formula, with a carboxylic acid or its derivative represented by formula (XI) or (ii) by acylating the compound (X') [i.e., the compound of formula (X) in which R 1 is H)] with a carboxylic acid or its derivative represented by formula (XI) and then causing a nitrogen-containing cyclic compound (IV) or is salt to act further.
- R, X and Y have the same meanings as defined above, Rs means a hydrogen atom or an alkyl, aryl or aralkyl group, and X" denotes a hydroxyl group or an eliminative substituent easily reactable with a hydroxyimino group.
- Illustrative of the eliminative group (X") easily reactable with a hydroxyimino group include cyano group, halogen atoms such as CI and Br, p-nitrophenoxy group, and those represented by the formula wherein R 6 means an alkyl, aryl, aralkyl, alkoxyl or aryloxyl group.
- reaction between the compound (Ib') or (X') with the carboxylic acid or its derivative represented by the formula (XI) can be conducted using any one of the various esterification processes described in "Compendium for Organic Synthesis” (WILEY-INTERSCIENCE, a division of John Wiley & Sons, Inc.) and the like.
- Examples include the process in which the compound (Ib') or (X') and the carboxylic acid represented by the formula (XI') [the compound of formula (XI) in which X" is OH] are condensed with diethyl cyanophosphonate (DEPC), diphenylphosphoryl azide (DPPA), dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 2-iodo-1-methylpyridinium iodide or the like, if necessary in the presence of an organic base such as triethylamine, pyridine, collidine, DBU or sodium acetate or an inorganic base such as potassium carbonate or sodium hydroxide; and the process in which the acid halide represented by the formula (XI") [the compound of (XI) in which X" is a halogen atom such as chlorine or bromine] is reacted to the compound (I
- the compounds (I) of the present invention obtained as described above can be reacted with various acids or alkylating or aralkylating agent to convert the compounds (I) to their pharmacologically acceptable salts, followed by purification by recrystallization or column chromatography and the like.
- Exemplary acids usable to convert the pyrroloazepine derivatives (I) to their salts include inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid and hydrobromic acid; and organic acids such as maleic acid, fumaric acid, tartaric acid, oxalic acid, lactic acid, citric acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, adipic acid, palmitic acid and tannic acid.
- inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid and hydrobromic acid
- organic acids such as maleic acid, fumaric acid, tartaric acid, oxalic acid, lactic acid, citric acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, adipic acid, palmitic acid and tannic acid.
- exemplary salts of the compounds (I) of the present invention include their quaternary ammonium salts, which are obtained by causing an alkylating agent.
- alkylating agent include C 1-10 alkyl halides, C 7 - 12 aralkyl halides, dialkyl sulfates and the like.
- Exemplary C 1-10 alkyl halides include methyl chloride, ethyl chloride, methyl bromide, ethyl bromide, methyl iodide and ethyl iodide and exemplary C 7 - 12 aralkyl halides include benzyl chloride and benzyl bromide, while illustrative dialkyl sulfates include dimethyl sulfate and diethyl sulfate.
- the pyrroloazepine derivatives (I) and their salts, which are obtained as described above, have anti-a, action and anti-serotonin action as will be demonstrated later by tests. Further, their LD so values are as high as at least 300 mg/kg (p.o) so that they have a high degree of safety.
- the compounds according to the present invention can therefore be used as therapeutics for circulatory diseases such as hypertension and congestive heart failure.
- the pyrroloazepine derivatives (I) and their salts are used as drugs, they can be administered in an effective dose as they are. As an alternative, they can also be formulated into various preparation forms by known methods and then administered.
- Exemplary preparation forms as drugs include orally administering preparation forms such as tablets, powders, granules, capsules and syrups as well as parenterally administering preparation forms such as injections and suppositories.
- preparation form such as tablets, powders, granules, capsules and syrups
- parenterally administering preparation forms such as injections and suppositories.
- a known liquid or solid extender or carrier usable for the formulation of the preparation form can be employed.
- extender or carrier examples include polyvinylpyrrolidone, arabic gum, gelatin, sorbit, cyclodextrin, tragacanth, magnesium stearate, talc, polyethylene glycol, polvinyl alcohol, silica, milk sugar, crystalline cellulose, sugar, starch, calcium phosphate, vegetable oil, carboxymethylcellulose, sodium laurylsulfate, water, ethanol, glycerin, mannitol, and syrup.
- a mixed solvent (400 m.e) of ethyl acetate and benzene (2:1 v/v) was added to the reaction mixture.
- the organic layer was washed successively with a saturated aqueous solution of sodium hydrogencarbonate, water (three times) and saturated saline, followed by drying over anhydrous sodium sulfate.
- the filtrate was saturated with sodium chloride, followed by extraction with ethyl acetate.
- the extract was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure, whereby crystals were obtained.
- reaction mixture was poured into 700 ml of ice water, followed by extraction with chloroform.
- the organic layer was washed with saturated saline (twice) and then dried over anhydrous sodium sulfate.
- reaction mixture was poured into 750 mt of ice water, followed by extraction with chloroform.
- the organic layer was washed with saturated saline (twice) and then dried over anhydrous sodium sulfate.
- the resultant solid was purified by chromatography on a silica gel column using as silica gel "Art. 9385" (product of Merk & Co.; the same silica gel was also used in the subsequent examples) (eluent: 3:2 mixed solvent of ethyl acetate and hexane), whereby 1.540 g of the title compound was obtained as a colorless solid (yield: 80%).
- reaction mixture was poured into 200 ml of 5% hydrochloric acid, followed by the addition of 500 m of a mixed solvent of ethyl acetate and benzene (2:1, v/v).
- a mixed solvent of ethyl acetate and benzene (2:1, v/v) was allowed to separate into an organic layer and a water layer.
- the organic layer was washed with water (three times) and saturated saline, and was then dried over anhydrous sodium sulfate.
- the solvent was distilled off under reduced pressure.
- the resultant oil was purified by chromatography on a silica gel column (eluent: 1:1 mixed solvent of ethyl acetate and hexane), whereby 3.907 g of the title compound were obtained as colorless crystals (yield: 97%).
- Compound Nos. 24, 25, 26, 27, 28 and 29 were obtained by using Compound No. 16 and 1,4-dibromobutane, (Z)-1,4-dichloro-2-butene, (E)-1,4-dichloro-2-butene, 1,4-dichloro-2-butyne, 1,3-dichloropropane and 1,5-dichloropentane in place of 1,4-dichlorobutane.
- Compound No. 35 was obtained from the combination of Compound 21 and 1,4-dibromobutane.
- the solvent was distilled off under reduced pressure and the resultant oil was purified by chromatography on a silica gel column (eluent: 7.5% methanolchloroform), whereby 3.84 g of a colorless oil were obtained (yield: 90%).
- the oil was crystallized when treated with isopropyl ether.
- Compound Nos. 36, 41, 37, 42, 43, 44, 45 and 47 were obtained by using Compound Nos. 22, 24, 28, 29, 30, 31, 32 and 34 in place of Compound No. 23 in the procedure of Example 17.
- reaction mixture was concentrated under reduced pressure, added with 500 mi of chloroform, washed with a 5% aqueous solution of hydrochloric acid, a half-saturated aqueous solution of potassium carbonate and saturated saline, and then dried over anhydrous sodium sulfate.
- reaction mixture was concentrated under reduced pressure.
- the residue was added with 20 ml of a half-saturated aqueous solution of potassium carbonate and was then extracted with chloroform.
- the extract was washed with saturated saline, followed by drying over anhydrous sodium sulfate.
- the solvent was distilled off under reduced pressure, followed by the addition of 600 mt of ethyl acetate to the residue.
- the organic layer was washed with 1 N-HCI (three times), H 2 0 and saturated saline and was then dried over anhydrous sodium sulfate.
- the solvent was distilled off under reduced pressure and the resultant pale yellow oil was purified by chromatography on a silica gel column (eluent: 2:3 mixed solvent of ethyl acetate and hexane), whereby 16.20 g of the title compound were obtained as a colorless oil.
- the oil was crystallized when treated in isopropyl ether (yield: 87%).
- Compound Nos. 52, 53, 54, 55, 72 and 78 were obtained from Compound No. 24 and 4-benzylpiperidine, 4-[bis(4-fluorophenyl)methylene]piperidine, a,a-bis(4-fluorophenyl)-4-piperidinemethanol, 4-(diphenylmethoxy)piperidine, 4-(4-methoxybenzoyl)piperidine and 3-benzoylpyrrolidine, respectively.
- Compound No. 48 was obtained from Compound No. 35 and 4-phenylpiperidine.
- Compound No. 73 was also obtained by using 4-(4-chlorobenzoyl)piperidine hydrochloride in place of 4-(4-fluorobenzoyl)piperidine hydrochloride.
- Compound No. 66 was obtained from Compound No. 47 and 4-(4-fluorobenzoyl)piperidine, and Compound Nos. 70 and 71 from Compound Nos. 24 and 41 and 4-benzoylpiperidine, respectively.
- Example 24 The reaction mixture was then post-treated and purified as in Example 24, whereby 230 mg of the title compound were obtained as colorless crystals (yield: 89%). Although the compound is sufficiently pure, it can be recrystallized from methanol-ethanol if necessary.
- Compound Nos. 80, 94 and 88 were obtained from 4-(4-fluorobenzoyl)piperidine hydrochloride and Compound Nos. 39, 31 and 33, respectively.
- Compound Nos. 77 and 84 were obtained from Compound No. 38 and 3-(4-fluorobenzoyl)-piperidine and 4-(4-fluorophenoxy)piperidine, respectively.
- the compound is sufficiently pure, it can be recrystallized from isopropyl alcohol-isopropyl ether if necessary.
- Example 34 The title compound was obtained from Compound No. 23 obtained in Example 14 and 4-cyano-4-phenylpiperidine hydrochloride in accordance with the procedure of Example 29 except that triethylamine was replaced by the same mole number of potassium carbonate.
- Example 34
- Compound No. 64 was also obtained from the combination of Compound No. 42 and 4-(4-fluorobenzoyl)piperidine hydrochloride.
- reaction mixture was added with 300 mt of a 3:1 (v/v) mixture of ethyl acetate and benzene, washed with a saturated aqueous solution of potassium carbonate, water (three times) and saturated saline, and then dried over anhydrous sodium sulfate.
- the reaction mixture was concentrated under reduced pressure and 600 m of a 3:1 (v/v) mixed solvent of ethyl acetate and benzene were added to the residue.
- the organic layer was washed with a 10% aqueous solution of citric acid, water (three times) and saturated saline and was then dried over anhydrous sodium sulfate.
- the solvent was thereafter distilled off under reduced pressure.
- the resulting brown oil was purified by chromatography on a silica gel column (eluent: 1:1 mixed solvent of ethyl acetate and hexane) and then recrystallized from isopropyl ether, whereby 5.604 g of the title compound were obtained (yield: 87%)
- the reaction mixture was concentrated under reduced pressure.
- the residue was added with 300 m l of a half-saturated aqueous solution of potassium carbonate, followed by the extraction with dichloromethane (200 ml x 3 times).
- the dichloromethane layers were combined, washed with 200 m of saturated saline, and then dried over anhydrous sodium sulfate.
- the solvent was distilled off under reduced pressure.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Hospice & Palliative Care (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
Description
- The present invention relates to novel pyrroloazepine derivatives, and more specifically to novel pyrroloazepine derivatives and salts thereof, said derivatives and salts having strong anti-ai action and anti-serotonin action but low toxicity and being useful as therapeutics for circulatory diseases such as hypertension and congestive heart failure, their preparation processes thereof and therapeutics for circulatory diseases, said therapeutics containing them as active ingredients.
- Numerous substances have heretofore been known as drugs which act on the circulatory system. Among these, a variety of substances have been developed as antihypertensive drugs.
- Of such antihypertensive drugs, α1-blockers represented by prazosin have such merits that (1) their antihypertensive action is strong and sure, (2) they do not give adverse influence to the lipidometabolic and glycometabolic systems and (3) they can be easily used for hypertensives having complication. Their development is hence actively under way. Clinically-applied examples of such α1-blockers include bunazosin, doxazosin, terazosin and urapidil in addition to prazosin.
- α1-Blockers are however accompanied by the drawback that they generally have side effects such as orthostatic disorder and reflex tachycardia, tend to induce orthostatic hypotension especially when administered to aged people and hence require attention.
- As a drug having less tendency of inducing such side effects of α1-blockers, ketanserin having both anti-serotonin action and anti-ai action has been developed as a drug effective for senile hypertension and the like.
- However, this ketanserin may not be able to exhibit, for example, sufficient hypotensive action in some instances, and its side effects to the central nervous system such as drowsiness and sedative action have posed problems.
- In view of the foregoing circumstances, the present inventors synthesized numerous compounds and investigated their pharmacological effects with a view toward obtaining drugs having both anti-serotonin action and anti-ai action, strong hypertensive action, and low side effects and toxicity.
- As a result, the compounds represented by the below-described formula (I) and having the pyrroloazepine structure have been found to meet the above requirements, leading to the completion of the present invention.
- This invention therefore provides a pyrroloazepine derivative represented by the following formula (I):
- The pyrroloazepine derivatives (I) and their pharmacologically acceptable salts according to the present invention are drugs having anti-ai action and anti-serotonin action and have a high degree of safety. They can therefore be used, for example, as novel therapeutics for circulatory diseases.
- In the pyrroloazepine derivative (I) of the present invention, preferred examples of group A include C3-6 alkenyl groups such as -CH2CH=CHCH2-, C3-6 alkynyl groups such as CH2C=CCH2-, and (CH2)n (n: 3-5). Preferred examples of group R include hydrogen atom, and methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and benzyl groups. In addition, preferred examples of R3 and Rs' include a phenyl group; a phenyl group substituted by one or more halogen atoms such as fluorine, chlorine and bromine, and C1-4 alkoxy groups such as methoxy and ethoxy groups; a benzyl group; and a diphenylmethyl group. When R3 and Rs' mean substituted aralkyl groups, each substituent may be bonded to either the aryl moiety or the alkyl moiety. When B stands for a substituted hydroxymethylene group, exemplary substituents include lower alkyl groups such as methyl, ethyl and propyl; a phenyl group; and a phenyl group substituted by one or more halogen atoms such as fluorine, chlorine and bromine and C1 -4 alkoxy groups such as methoxy and ethoxy groups. Further, examples of the substituted or unsubstituted, cyclic or acyclic acetal represented by B include
- Where compounds according to the present invention have isomers, it is to be noted that these isomers are all embraced by the present invention. For example, when there is a hydroxyimino group or an 0- substituted hydroxyimino group at 4-position of the pyrroloazepine ring, there are both an (E)-isomer and a (Z) isomer with respect to the group. The compounds of the present invention also include these individual isomers and their mixtures.
- The pyrroloazepine derivatives (I) according to the present invention can be prepared by a desired conventional method. However, the pyrroloazepine derivatives (I) are preferably prepared, for example, by any of the following processes:
- (1) Among the pyrroloazepine derivatives (I), the compounds (la) in which Z represents O can each be obtained in accordance with the following reaction scheme, namely, by converting the compound represented by formula (II) to the compound represented by formula (III) and then reacting the nitrogen-containing cyclic compound represented by formula (IV) or a salt thereof with the compound (III).
- The conversion from the compound (II) to the compound (III) is effected by causing the compound represented by formula (V) to act on the compound (II) in the presence of an organic or inorganic base. Examples of the substituent, which is easily replaceable with an amino group, as group X in the compound (V) include halogen atoms such as chlorine and bromine atoms, methanesulfonyl group and p-toluenesulfonyl group. Any solvent can be used in this reaction as long as it does not take part in the reaction. Illustrative solvents include dimethylformamide, acetonitrile, dimethylsulfoxide, tetrahydrofuran, dioxane and acetone. Further, exemplary organic or inorganic bases include triethylamine, pyridine, collidine, 1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU) sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium ethoxide, and potassium t-butoxide. The reaction is conducted at -20 C to the reflux temperature.
- To prepare the compound (la) by reacting the compound (III) with the nitrogen-containing cyclic compound (IV), it is only necessary to react at room temperature to 150°C the nitrogen-containing cyclic compound (IV) or an organic acid or inorganic acid salt thereof with the compound (III), optionally together with an organic base such as triethylamine, pyridine, collidine, DBU or potassium t-butoxide or an inorganic base such as potassium carbonate, sodium carbonate, potassium hydroxide or sodium hydroxide, optionally after adding an iodide such as sodium iodide or potassium iodide.
- Examples of the nitrogen-containing cyclic compound (IV) include 4-phenylpiperidine, 4-benzylpiperidine, 4-[bis(4-fluorophenyl)methylene]piperidine, α,α-bis-4-(fluorophenyl)-4-piperidinemethanol, 4-(diphenylmethoxy)piperidine, 4-cyano-4-phenylpiperidine, 4-4-(fluorobenzoyl)piperidine, 4-benzoylpiperidine, 4-(4-methoxybenzoyl)piperidine, 4-(4-chlorobenzoyl)piperidine, 3-(4-fluorobenzoyl)piperidine, 3-benzoylpyrrolidine, 3-(4-fluorobenzoyl)pyrrolidine, 4-(4-fluorophenoxy)piperidine, 4-[(4-fluorophenyl)thio]piperidine, 4-[-(4-fluorophenyl)-sulfinyl]piperidine, 4-[(4-fluorophenyl)sulfonyl]piperidine, and 4-(4-fluorobenzoyl)piperidine ethyleneacetal. They are all either known compounds or compounds which can be readily prepared by a known process or a process similar to the known process.
- Incidentally, among the compounds (II) employed as starting materials in the above reaction, the compound in which R is H has been known but the remaining compounds are novel compounds. These novel compounds can each be prepared in accordance with the following reaction scheme, namely, by reacting a pyrrole-2-carboxylic acid represented by the formula (VI) or a derivative thereof with a ,8-amino acid represented by the formula (VII) or a derivative thereof or an organic or inorganic salt of the p-amino acid or the derivative thereof and optionally removing the protecting group, thereby obtaining the compound represented by the formula (VIII) and then ring-closing this compound.
- Examples of the substituent easily replaceable with an amino group as represented by W in the compound (VI) include halogen atoms, carboxylic acid residue and the like. On the other hand, as the carboxyl-protecting group, it is possible to use, in addition to lower alkyl groups such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl and t-butyl and C7-20 aralkyl groups such as benzyl and 9-anthrylmethyl, the conventional protecting groups described by T.W. Greene in "Protective Group in Organic Synthesis" (John Wiley & Sons, Inc.) and the like. For the synthesis of the compounds (VIII), it is possible to use any one of the various processes disclosed in "Compendium for Organic Synthesis" (WILEY-INTERSCIENCE, a division of John Wiley & Sons, Inc.) and the like. Exemplary processes include the process in which pyrrole-2-carboxylic acid of the compound (VI) in which W is OH is treated with an organic compound such as diethyl cyanophosphonate (DEPC), diphenylphosphoryl azide (DPPA), dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride or 2-iodo-1-methylpyridinium iodide or an inorganic compound such as silicon tetrachloride or tin tetrachloride, if necessary, in the presence of an organic or inorganic base; and the process in which pyrrole-2-carboxylic acid is reacted after converting it to its active ester such as its acid halide, symmetric acid anhydride, mixed acid anhydride or p-nitrophenyl ester or to a like compound.
- Each compound (VIII) thus obtained is subjected to a cyclizing reaction, optionally after removing the protecting group by virtue of a suitable method such as the action of an acid or a base, or catalytic reduction. This cyclizing reaction is conducted by treating the compound (VIII) together with an organic acid such as methanesulfonic acid, an inorganic acid such as sulfuric acid or polyphosphoric acid or a mixture of such an organic or inorganic acid and diphosphorus pentoxide at room temperature to 170° C, preferably at 80-120* C. In this case, a solvent which does not take part in the reaction may be added as needed. As an alternative, the cyclizing reaction can also be practiced by treating the compound (VIII) with oxalyl chloride, thionyl chloride, thionyl bromide, oxalyl bromide, phosgene, phosphorus trichloride, phosphorus tribromide, phosphoryl chloride, phosphoryl bromide or the like, optionally in the presence of a catalyst to convert the compound (VIII) to its corresponding acid halide and then treating the acid halide at -20 C to reflux temperature in the presence of a Lewis acid such as aluminum chloride, aluminum bromide, boron trifluorideether complex or tin tetrachloride in a solvent such as dichloromethane, 1,2-dichloroethane or nitromethane or heating the acid halide in acetic acid.
- The compounds (II) obtained in the above manner can be used directly as starting materials for the preparation of the compounds (la) of the present invention. They can also be used after purification by a conventional purification method, for example, by recrystallization or column chromatography if necessary.
- (2) Among the pyrroloazepine derivatives (I), the compounds (Ib) in which Z is represented by NOR1can each be prepared in accordance with the following reaction formula, namely, (i) by causing a hydroxyamine represented by the formula (IX) or a derivative thereof or a salt of the hydroxylamine or the derivative to act on the compound (la) obtained by the above-described reaction or (ii) by causing the hydroxylamine or its derivative (IX) or a salt of the hydroxylamine or the derivative to act on the compound (III) and then causing a nitrogen-containing cyclic compound (IV) or a salt thereof to act further.
- The reaction between the compound (la) or (III) and the hydroxylamine or its derivative (IX) is practiced, if necessary, in the presence of an organic base such as pyridine, triethylamine, collidine, DBU or sodium acetate or an inorganic base such as potassium carbonate or sodium hydroxide. The hydroxylamine or its derivative (IX) may also be used in the form of an organic acid salt or an inorganic acid salt.
- The compound (X) obtained by the reaction of the compound (III) with the compound (IX) can be reacted further with the nitrogen-containing cyclic compound (IV) by the method described above, whereby the compound (X) can be converted to the compound (Ib).
- Upon preparation of the compound (Ib), it is determined depending on the structure and properties of the nitrogen-containing cyclic compound (IV) whether the hydroxylamine or its derivative (IX) should be reacted to the compound (III) or to the compound (la). Where there is a group reactive to the hydroxylamine or its derivative (IX), such as a carbonyl group, in the nitrogen-containing cyclic compound (IV), it is desirable to choose the process that the hydroxylamine or its derivative (IX) is reacted to the compound (III).
- (3) Among the pyrroloazepine derivatives (I), the compounds (Ic) in which X is represented by
-
- The reaction between the compound (Ib') or (X') with the carboxylic acid or its derivative represented by the formula (XI) can be conducted using any one of the various esterification processes described in "Compendium for Organic Synthesis" (WILEY-INTERSCIENCE, a division of John Wiley & Sons, Inc.) and the like.
- Examples include the process in which the compound (Ib') or (X') and the carboxylic acid represented by the formula (XI') [the compound of formula (XI) in which X" is OH] are condensed with diethyl cyanophosphonate (DEPC), diphenylphosphoryl azide (DPPA), dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 2-iodo-1-methylpyridinium iodide or the like, if necessary in the presence of an organic base such as triethylamine, pyridine, collidine, DBU or sodium acetate or an inorganic base such as potassium carbonate or sodium hydroxide; and the process in which the acid halide represented by the formula (XI") [the compound of (XI) in which X" is a halogen atom such as chlorine or bromine] is reacted to the compound (Ib') or (X'), if necessary in the presence of the above-described organic or inorganic base.
- If necessary, the compounds (I) of the present invention obtained as described above can be reacted with various acids or alkylating or aralkylating agent to convert the compounds (I) to their pharmacologically acceptable salts, followed by purification by recrystallization or column chromatography and the like.
- Exemplary acids usable to convert the pyrroloazepine derivatives (I) to their salts include inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid and hydrobromic acid; and organic acids such as maleic acid, fumaric acid, tartaric acid, oxalic acid, lactic acid, citric acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, adipic acid, palmitic acid and tannic acid.
- In addition, other exemplary salts of the compounds (I) of the present invention include their quaternary ammonium salts, which are obtained by causing an alkylating agent. Usable examples of the alkylating agent include C1-10 alkyl halides, C7-12 aralkyl halides, dialkyl sulfates and the like. Exemplary C1-10 alkyl halides include methyl chloride, ethyl chloride, methyl bromide, ethyl bromide, methyl iodide and ethyl iodide and exemplary C7-12 aralkyl halides include benzyl chloride and benzyl bromide, while illustrative dialkyl sulfates include dimethyl sulfate and diethyl sulfate.
- The pyrroloazepine derivatives (I) and their salts, which are obtained as described above, have anti-a, action and anti-serotonin action as will be demonstrated later by tests. Further, their LDso values are as high as at least 300 mg/kg (p.o) so that they have a high degree of safety. The compounds according to the present invention can therefore be used as therapeutics for circulatory diseases such as hypertension and congestive heart failure.
- When the pyrroloazepine derivatives (I) and their salts are used as drugs, they can be administered in an effective dose as they are. As an alternative, they can also be formulated into various preparation forms by known methods and then administered.
- Exemplary preparation forms as drugs include orally administering preparation forms such as tablets, powders, granules, capsules and syrups as well as parenterally administering preparation forms such as injections and suppositories. Whichever preparation form is used, a known liquid or solid extender or carrier usable for the formulation of the preparation form can be employed.
- Examples of such extender or carrier include polyvinylpyrrolidone, arabic gum, gelatin, sorbit, cyclodextrin, tragacanth, magnesium stearate, talc, polyethylene glycol, polvinyl alcohol, silica, milk sugar, crystalline cellulose, sugar, starch, calcium phosphate, vegetable oil, carboxymethylcellulose, sodium laurylsulfate, water, ethanol, glycerin, mannitol, and syrup.
- The present invention will next be described in further detail by the following examples and tests.
- A solution of 5.34 g (48.1 mmol) of pyrrole-2-carboxylic acid and 18.59 g (52.9 mmol) of β-alanine benzyl ester tosylate in 100 m of dimethylformamide (DMF) was cooled to 0°C, followed by the addition of a solution of 9.42 g (57.7 mmol) of diethyl cyanophosphate in 20 mt of DMF under stirring. After a solution of 11.68 g (115.4 mmol) of triethylamine in 20 m of DMF was gradually added further dropwise, the resultant mixture was stirred for 40 hours at room temperature.
- A mixed solvent (400 m.e) of ethyl acetate and benzene (2:1 v/v) was added to the reaction mixture. The organic layer was washed successively with a saturated aqueous solution of sodium hydrogencarbonate, water (three times) and saturated saline, followed by drying over anhydrous sodium sulfate.
- The solvent was distilled off under reduced pressure and the resultant solid was recrystallized from chloroform-isopropyl ether, whereby 11.65 g of the title compound were obtained (yield: 95%). Appearance: Colorless prism crystals. Melting point: 82-83° C.
- A solution of 50.0 g (450 mmol) of pyrrole-2-carboxylic acid and 64.9 g (495 mmol) of ethyl 3-(methylamino)propionate in 200 mℓ of dimethylformamide (DMF) was cooled to 0°C, followed by the addition of a solution of 80.8 g (495 mmol) of diethyl cyanophosphate in 100 mℓ of DMF under stirring. After a solution of 50.1 g (495 mmol) of triethylamine in 100 m of DMF was added dropwise at the same temperature over 1 hour, the resultant mixture was stirred for 18 hours at room temperature.
- To an oil obtained by concentrating the reaction mixture under reduced pressure, 1200 mℓ of a mixed solvent of ethyl acetate and benzene (3:1 v/v) was added. The organic layer was washed successively with a saturated aqueous solution of potassium carbonate, water, 5% hydrochloric acid solution (twice) and saturated saline, followed by drying over anhydrous sodium sulfate. To an oil obtained by distilling off the solvent under reduced pressure, isopropyl ether (200 mℓ) and hexane (1000 mi) were added. After the resultant mixture was shaken, it was allowed to stand for one day.
- Precipitated crystals were collected by filtration and then dried under reduced pressure, whereby 87.5 g of the title compound were obtained as colorless glossy crystalline powder (yield: 87%).
- Although this compound is sufficiently pure, it can be recrystallized from isopropyl ether if necessary. Appearance: Colorless prism crystals.
Melting point: 57-58 C. - The following compounds (Compound No. 3, 4, 5 and 7) were obtained by using ethyl 3-(ethylamino)-propionate, ethyl 3-(propylamino)propionate, ethyl 3-(isopropylamino)propionate and ethyl 3-(benzylamino)-propionate in place of ethyl 3-(methylamino)propionate in the procedure described in Example 2.
- Ethyl 3-(N-ethyl-2-pyrrolecarboxamido)propionate
- Ethyl 3-(N-propyl-2-pyrrolecarboxamido)propionate
- Ethyl 3-(N-isopropyl-2-pyrrolecarboxamido)propionate
- Ethyl 3-(N-benzyl-2-pyrrolecarboxamido)propionate
- Synthesis of ethyl 3-(N-methyl-2-pyrrolecarboxamido)propionate (Compound No. 2) (alternative process)
- To a solution of 5.56 g (50 mmol) of pyrrole-2-carboxylic acid and one droplet of DMF in 50 m of tetrahydrofuran (THF) were added dropwise 6.54 m (75 mmol) of oxalyl chloride under stirring and ice cooling at 0° C, and the resultant mixture was stirred for 2 hours at room temperature. The reaction mixture was concentrated under reduced pressure so that crystals of the acid chloride were obtained.
- A solution of the above-obtained acid chloride in 40 m of benzene was slowly added dropwise under cooling and stirring to a solution of 6.56 g (50 mmol) of ethyl (3-methylamino)propionate and 4.85 mℓ (60 mmol) of pyridine in 20 mℓ of benzene. The resulting mixture was stirred for 30 minutes at the same temperature and for additional 18 hours at room temperature. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Upon recrystallization of the resultant crystals from isopropyl ether, 10.2 g of the title compound were obtained (yield: 91 %).
- Synthesis of ethyl 3-(N-butyl-2-pyrrolecarboxamido)propionate(Compound No. 6)
- The title compound was obtained by using ethyl 3-(butylamino)propionate in place of ethyl 3-(methylamino)propionate in the procedure described in Example 4.
- Synthesis of 3-(N-methyl-2-pyrrolecarboxamide)propionic acid (Compound 9)
- A mixture of 37.00 g (165 mmol) of Compound No. 2 obtained in Example 2, 413 m (826 mmol) of 2N aqueous solution of sodium hydroxide and 20 m ℓ of ethanol was stirred for 4 hours at room temperature. The reaction mixture was cooled, and 80 m of concentrated hydrochloric acid were added under stirring, followed by further stirring. Precipitated crystals were then collected by filtration.
- The filtrate was saturated with sodium chloride, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure, whereby crystals were obtained.
- Both crystals were combined and recrystallized from ethyl acetate, whereby 27.69 g of the title compound were obtained (yield: 86%). Appearance: Colorless prism crystals. Melting point: 125-1270 C.
- The following compounds (Compound Nos. 10, 11, 12, 13 and 14) were obtained by using Compound Nos. 3, 4, 5, 6 and 7 in place of Compound No. 2 in the procedure described in Example 6.
- 3-(N-Ethyl-2-pyrrolecarboxamido)propionic acid
- 3-(N-propyl-2-pyrrolecarboxamido)propionic acid
- 3-(N-Isopropyl-2-pyrrolecarboxamido)propionic acid
- 3-(N-Butyl-2-pyrrolecarboxamido)propionic acid
- 3-(N-Benzyl-2-pyrrolecarboxamido)propionic acid
- Synthesis of 3-(2-pyrrolecarboxamido)propionic acid (Compound No. 8)
- Hydrogen was blown at atmospheric pressure into a suspension of 10.00 g (39.3 mmol) of Compound No. 1 obtained in Example 1 and 2.00 g of 5% palladium-carbon in 300 mℓ of THF while the suspension was stirred. After the full consumption of the starting material was confirmed by thin layer chromatography on silica gel (about 1 hour), the reaction mixture was filtered and an insoluble matter was washed with THF.
- The filtrate and the washing were combined, and the solvent was distilled off under reduced pressure. The resulting solid was recrystallized from acetonitrile, whereby 5.61 g of the title compound were obtained (yield: 78%).
- Appearance: Colorless prism crystals.
- Melting point: 148-150 C.
- Synthesis of 7-methyl-6,7-dihydropyrrolo[2,3-c]azepine-4,8(1 H,5H)-dione (Compound No. 16)
- A mixture of 7.00 g of Compound No. 9 obtained in Example 6 and 250 g of polyphosphoric acid (about 80%) was vigorously stirred for 30 minutes by a mechanical stirrer over an oil bath maintained at 100° C.
- The reaction mixture was poured into 700 mℓ of ice water, followed by extraction with chloroform. The organic layer was washed with saturated saline (twice) and then dried over anhydrous sodium sulfate.
- The solvent was distilled off under reduced pressure, whereby 5.58 g of the title compound were obtained as pale brown crystals (yield: 88%).
- Although this compound is sufficiently pure, it can be recrystallized from chloroform-isopropyl ether if necessary.
- Appearance: Colorless needle crystals.
- Melting point: 175-177° C.
- The following compounds (Compound Nos. 15, 17, 18, 19 and 21) were obtained by using Compound Nos. 8, 10, 11, 12 and 14 in place of Compound No. 9 in the procedure of Example 9.
- 6,7-Dihydropyrrolo[2,3-c]azepine-4,8(1 H,5H)-dione
- 7-Ethyl-6,7-dihydropyrrolo[2,3-c]azepine-4,8-(1 H,5H)-dione
- 7-Propyl-6,7-dihydropyrrolo[2,3-e]azepine-4,8-(1 H,5H)-dione
- 7-Isopropyl-6,7-dihydropyrrolo[2,3-c]azepine-4,8(1 H,5H)-dione
- 7-Benzyl-6,7-dihydropyrrolo[2,3-c]azepine-4,8-(1 H,5H)-dione
- Synthesis of 7-butyl-6,7-dihydropyrrolo[2,3-c]azepine-4,8(1 H,5H)-dione (Compound No. 20)
- A mixture of 10.0 g (42.0 mmol) of Compound No. 13 and 200 g of polyphosphoric acid (about 80%) was vigorously stirred for 30 minutes by a mechanical stirrer over an oil bath maintained at 80° C. After 3.02 g of diphosphorus pentaoxide were added and the resultant mixture was stirred for 1 minute, 10.0 g (42.0 mm) of Compound No.13 were added and the mixture thus formed was vigorously stirred for 30 minutes at the same temperature.
- The reaction mixture was poured into 750 mt of ice water, followed by extraction with chloroform. The organic layer was washed with saturated saline (twice) and then dried over anhydrous sodium sulfate.
- The solvent was distilled off under reduced pressure, whereby 16.73 g of the title compound were obtained as pale brown crystals (yield: 91%). Appearance: Pale brown needle crystals.
- Melting point: 115-1180 C.
- Synthesis of 7-methyl-6,7-dihydropyrrolo[2,3-c]azepine-4,8-(lH,5H)-dione (Compound No. 16) (alternative process)
- A mixture of 329 mg (2 mmol) of Compound No. 9 obtained in Example 6 and 15 mℓ of methanesulfonic acid was stirred for 40 minutes at 100°C. The reaction mixture was allowed to cool down and then poured into 200 mℓ of ice water. The resultant mixture was adjusted to about pH 5 with potassium carbonate and then saturated with sodium chloride. The aqueous layer was extracted with chloroform. THe extract was washed with saturated saline and then dried over anhydrous sodium sulfate.
- The solvent was distilled off under reduced pressure, whereby 337 mg of the title compound were obtained as a pale brown solid.
- Although this compound is sufficiently pure, it can be recrystallized from chloroform-isopropyl ether if necessary.
- Synthesis of 7-ethyl-6,7-dihydropyrrolo[2,3-c]azepine-4,8(1 H,SH)-dione (Compound No. 17) (alternative process)
- To a solution of 2.104 g (10 mmol) of Compound No. 10 in 30 mℓ of THF, 1.523 g (12 mmol) of oxalyl chloride and 1 droplet of DMF were added at room temperature under stirring. The resultant mixture was stirred for 3 hours at the same temperature, and the solvent was distilled off under reduced pressure.
- The residue was then dissolved in 100 m ℓ of 1,2-dichloroethane, followed by the addition of 4.00 g (30 mmol) of ground aluminum chloride. After the reaction mixture was heated at 50-60° C for 2 hours, the reaction mixture was stirred for 20 hours at room temperature. The reaction mixture was poured into 300 m of ice water. The mixture thus prepared was allowed to separate into water and organic layers. The aqueous layer was extracted with chloroform. The extract and the organic layer were combined together, washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure.
- The resultant solid was purified by chromatography on a silica gel column using as silica gel "Art. 9385" (product of Merk & Co.; the same silica gel was also used in the subsequent examples) (eluent: 3:2 mixed solvent of ethyl acetate and hexane), whereby 1.540 g of the title compound was obtained as a colorless solid (yield: 80%).
- Although this compound is sufficiently pure, it can be recrystallized from isopropanol if necessary. Appearance: Colorless needle crystals.
- Melting point: 131-1330 C.
- Synthesis of 1-(4-chlorobutyl)-7-methyl-6,7-dihydropyrrolo[2,3-c]azepine-4,8(1H,5H)-dione (Compound 23)
- A suspension of 2.67 (15 mmol) of Compound No. 16 obtained in Example 9, 7.62 g (60 mmol) of 1,4-dichlorobutane and 8.29 g (60 mmol) of potassium carbonate in 150 m of DMF was stirred at 80° C for 5 hours.
- The reaction mixture was poured into 200 mℓ of 5% hydrochloric acid, followed by the addition of 500 m of a mixed solvent of ethyl acetate and benzene (2:1, v/v). The resultant mixture was allowed to separate into an organic layer and a water layer. The organic layer was washed with water (three times) and saturated saline, and was then dried over anhydrous sodium sulfate.
- The solvent was distilled off under reduced pressure. The resultant oil was purified by chromatography on a silica gel column (eluent: 1:1 mixed solvent of ethyl acetate and hexane), whereby 3.907 g of the title compound were obtained as colorless crystals (yield: 97%).
- Although this compound is sufficiently pure, it can be recrystallized from ethyl acetate-hexane if necessary.
- Appearance: Colorless prism crystals.
- Melting point: 59.0-60.5 C.
- Compound Nos. 22, 30, 31, 32 and 34 were obtained by using Compound Nos. 15, 17, 18, 19 and 21 in place of Compound No. 16 in the procedure of Example 14.
- Compound Nos. 24, 25, 26, 27, 28 and 29 were obtained by using Compound No. 16 and 1,4-dibromobutane, (Z)-1,4-dichloro-2-butene, (E)-1,4-dichloro-2-butene, 1,4-dichloro-2-butyne, 1,3-dichloropropane and 1,5-dichloropentane in place of 1,4-dichlorobutane.
- Compound No. 35 was obtained from the combination of Compound 21 and 1,4-dibromobutane.
- 1-(4-Chlorobutyl)-6,7-dihydropyrrolo[2,3-c]azepine-4,8(1 H,5H)-dione
- 1-(4-Chlorobutyl)-7-ethyl-6,7-dihydropyrrolo[2,3-c]azepine-4,8(1 H,5H)-dione
- 1-(4-Chlorobutyl)-7-propyl-6,7-dihydropyrrolo[2,3-c]azepine-4,8(1 H,5H)-dione
- 1-(4-Chlorobutyl)-7-isopropyl-6,7-dihydropyrrolo[2,3-c]azepine-4,8(1 H,5H)-dione
- 7-Benzyl-1-(4-chlorobutyl)-6,7-dihydropyrrolo[2,3-c]azepine-4,8(1 H,5H)-dione
- 1-(4-Bromobutyl)-7-methyl-6,7-dihydropyrrolo[2,3-c]azepine-4,8(1 H,5H)-dione
- 1-(4-Chloro-(Z)-2-butenyl)-7-methyl-6,7-dihydropyrrolo[2,3-c]azepine-4,8(1 H,5H)-dione
- 1-(4-Chloro-(E)-2-butenyl)-7-methyl-6,7-dihydropyrrolo[2,3-c]azepine-4,8(1 H,5H)-dione
- 1-(4-Chloro-2-butynyf)-7-methyl-6,7-dihydropyrrolo[2,3-c]azepine-4,8(1 H,5H)-dione
- 1-(3-Chloropropyl)-7-methyl-6,7-dihydropyrrolo[2,3-c]azepine-4,8(1 H,5H)-dione
- 1-(5-Chloropentyl)-7-methyl-6,7-dihydropyrrolo[2,3-c]azepine-4,8(1 H,SH)-dione
- 7-Benzyl-1-(4-bromobutyl)-6,7-dihydropyrrolo[2,3-c]azepine-4,8(1 H,5H)-dione
- Synthesis of 7-butyl-1-(4-chlorobutyl)-6,7-dihydropyrrolo[2,3-c]azepine-4,8(1 H,SH)dione (Compound No. 33)
- A suspension of 16.47 g (74.48 mmol) of Compound No. 20 obtained in Example 11, 38.46 g (224 mmol) of 1-bromo-4-chlorobutane and 31.00 g (224 mmol) of potassium carbonate in 200 m of acetone was stirred for 20 hours.
- The reaction mixture was filtered to remove any insoluble matter and the solvent and excess 1-bromo-4-cholorobutane were distilled off under reduced pressure, whereby 22.0 g of the title compound were obtained (yield: 98%).
- Appearance: Colorless oil.
- Synthesis of 1-(4-chlorobutyl)-4-hydroxyimino-7-methyl-6,7-dihydropyrrolo[2,3-c]azepine-8(1 H,5H)-one (Compound No. 38)
- A solution of 4.031 g (15 mmol) of Compound No. 23 obtained in Example 14 and 5.212 g (75 mmol) of hydroxylamine hydrochloride in 90 m of pyridine was stirred for 18 hours at room temperature.
- After the reaction mixture was concentrated under reduced pressure, toluene was added, followed by concentration again under reduced pressure. The residue was added with 200 mℓ of a 10% aqueous solution of citric acid and then extracted with chloroform. The extract was washed with saturated saline and then dried over anhydrous sodium sulfate.
- The solvent was distilled off under reduced pressure and the resultant oil was purified by chromatography on a silica gel column (eluent: 7.5% methanolchloroform), whereby 3.84 g of a colorless oil were obtained (yield: 90%). The oil was crystallized when treated with isopropyl ether.
- Although this compound is sufficiently pure, it can be recrystallized from ethyl acetate if necessary. Appearance: Colorless needle crystals. Melting point: 113.0-114.0 C. Example 18
- Compound Nos. 36, 41, 37, 42, 43, 44, 45 and 47 were obtained by using Compound Nos. 22, 24, 28, 29, 30, 31, 32 and 34 in place of Compound No. 23 in the procedure of Example 17.
- 1-(4-Chlorobutyl)-4-hydroxyimino-6,7-dihydropyrrolo[2,3-c]azepine-8(1 H,5H)-one
- 1-(3-Chloropropyl)-4-hydroxyimino-7-methyl-6,7-dihydropyrrolo[2,3-c]azepine-8(1 H,5H)-one
- 1-(4-Bromobutyl)-4-hydroxyimino-7-methyl-6,7-dihydropyrrolo[2,3-c]azepine-8(1 H,5H)-one
- 1-(5-Chloropentyl)-4-hydroxyimino-7-methyl-6,7-dihydropyrrolo[2,3-c]azepine-8(1 H,5H)-one
- 1-(4-Chlorobutyl)-7-ethyl-4-hydroxyimino-6,7-dihydropyrrolo[2,3-c]azepine-8(1 H,5H)-one
- 1-(4-Chlorobutyl)-4-hydroxyimino-7-propyl-6,7-dihydropyrrolo[2,3-c]azepine-8(1 H,5H)-one
- 1-(4-Chlorobutyl)-4-hydroxyimino-7-isopropyl-6,7-dihydropyrrolo[2,3-c]azepine-8(1 H,5H)-one
- 7-Benzyl-1-(4-chlorobutyl)-4-hydroxyimino-6,7-dihydropyrrolo[2,3-c]azepine-8(1 H,5H)-one
- Synthesis of 7-butyM -(4-ch!orobuty!)-4-hydroxyim!no-6,7-dihydropyrro!o[2,3-c]azepine-8(1 H,5H)-one (Compound No. 46)
- A solution of 21.0 g (67.6 mmol) of Compound No. 33 obtained in Example 16, 14.1 g (203 mmol) of hydroxylamine hydrochloride and 16.6 g (203 mmol) of anhydrous sodium acetate in 150 mi of methanol was stirred for 24 hours at room temperature.
- The reaction mixture was concentrated under reduced pressure, added with 500 mi of chloroform, washed with a 5% aqueous solution of hydrochloric acid, a half-saturated aqueous solution of potassium carbonate and saturated saline, and then dried over anhydrous sodium sulfate.
- The solvent was distilled off under reduced pressure, whereby 19.0 g of the title compound were obtained as pale brown crystals (yield: 86%).
- Although this compound is sufficiently pure, it can be recrystallized from ethanol if necessary. Appearance: Pale brown needle crystals. Melting point: 133-1360 C.
- Synthesis of 1-(4-chlorobutyl)-4-methoxyimino-7-methyl-6,7-dihydropyrrolo[2,3-c]azepine-8(1 H,5H)-one (Compound No. 39)
- A solution of 210 mg (0.74 mmol) of Compound No. 23 obtained in Example 14 and 68 mg (0.82 mmol) of 0-methylhydroxylamine hydrochloride in 10 mℓ of pyridine was stirred for 4 hours at 80° C.
- The reaction mixture was concentrated under reduced pressure. The residue was added with 20 mℓ of a half-saturated aqueous solution of potassium carbonate and was then extracted with chloroform. The extract was washed with saturated saline, followed by drying over anhydrous sodium sulfate.
- The solvent was distilled off under reduced pressure and the resultant oil was purified by chromatography on a silica gel column (eluent: 3:7 mixed solvent of ethyl acetate and hexane), whereby 104 mg of the title compound were obtained (yield: 47%).
- Appearance: Colorless oil.
- Synthesis of 4-benzyloxyimino-1-(4-chlorobutyl)-7-methyl-6,7-dihydropyrrolo[2,3-c]azepine-8(1H,5H)-one (Compound No. 40)
- A suspension of 13.44 g (50 mmol) of Compound 23 obtained in Example 14, 8.20 g (100 mmol) of sodium acetate and 15.96 g (100 mmol) of o-benzylhydroxylamine hydrochloride in 250 m of methanol was stirred for 4 hours at room temperature.
- The solvent was distilled off under reduced pressure, followed by the addition of 600 mt of ethyl acetate to the residue. The organic layer was washed with 1 N-HCI (three times), H20 and saturated saline and was then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the resultant pale yellow oil was purified by chromatography on a silica gel column (eluent: 2:3 mixed solvent of ethyl acetate and hexane), whereby 16.20 g of the title compound were obtained as a colorless oil. The oil was crystallized when treated in isopropyl ether (yield: 87%).
- Although this compound is sufficiently pure, it can be recrystallized from isopropyl ether if necessary. Appearance: colorless prism crystals.
- Melting point: 62-64 C
- Synthesis of 1-[4-[4-(4-fluorobenzoyl)piperidin-1-yl]butyl]-7-methyl-6,7-dihydropyrrolo[2,3-c]azepine-4,8-(1H,5H)-dione (Compound No. 60)
- A suspension of 1.57 g (5 mmol) of Compound No. 24 obtained in Example 15, 2.07 g (10 mmol) of 4-(4-fluorobenzoyl)piperidine and 1.38 g (10 mmol) of potassium carbonate in 60 mi of DMF was stirred for 20 hours at 80° C. After allowed to cool down, the reaction mixture was filtered. A solid matter was washed with ethyl acetate. The filtrate and the washing were combined together, followed by concentration under reduced pressure. The residue was added with 400 m of a 3:1 (v/v) mixed solvent of ethyl acetate and benzene. The organic layer was washed with water (three times) and saturated saline, and then dried over anhydrous sodium sulfate.
- The solvent was distilled off under reduced pressure and the resultant brown oil was purified by chromatography on a silica gel column (eluent: 5% methanol-chloroform), whereby 1.89 g of the title compound were obtained (yield: 86%).
- Appearance: Yellow oil.
- Compound Nos. 67, 68 and 69 were obtained by using Compound Nos. 25, 26 and 27 in place of Compound No. 24 in the procedure described in Example 22.
- Further, Compound Nos. 52, 53, 54, 55, 72 and 78 were obtained from Compound No. 24 and 4-benzylpiperidine, 4-[bis(4-fluorophenyl)methylene]piperidine, a,a-bis(4-fluorophenyl)-4-piperidinemethanol, 4-(diphenylmethoxy)piperidine, 4-(4-methoxybenzoyl)piperidine and 3-benzoylpyrrolidine, respectively.
- Further, Compound No. 48 was obtained from Compound No. 35 and 4-phenylpiperidine.
- 1-[4-[4-(4-Fluorobenzoyl)piperidin-1-yl]-(Z)-2-butenyl]-7-methyl-6,7-dihydropyrrolo[2,3-c]azepine-4,8(1 H,5H)-dione
- 1-[4-[4-(4-Fluorobenzoyl)piperidin-1-yl]-(E)-2-butenyl]-7-methyl-6,7-dihydropyrrolo[2,3-c]azepine-4,8(1H,5H)-dione
- 1-[4-[4-(4-Fluorobenzoyl)piperidin-1-yl]-2-butynyl]-7-methyl-6,7-dihydropyrrolo[2,3-c]azepine-4,8(1H,5H)-dione
- 1-[4-(4-Benzylpiperidin-1-yl)butyl]-7-methyl-6,7-dihydropyrrolo[2,3-c]azepine-4,8(1 H,5H)-dione
- 1-[4-[4-[Bis(4-fluorophenyl)methylene]piperidin-1-yl)butyl]-7-methyl-6,7-dihydropyrrolo[2,3-c]azepine-4,8-(1 H,5N)-dione
- i-[4-[4-[Bis(4-fluorophenyl)hydroxymethyl]piperidin-1-yl)butyl]-7-methyl-6,7-dihydropyrrolo[2,3-c]azepine-4,8(1 H,5H)-dione
- 1-[4-[4-(Diphenylmethoxy)piperidin-1-yl)butyl]-7-methyl-6,7-dihydropyrrolo[2,3-c]azepine-4,8(1 H,5H)-dione
- 1-[4-[4-(4-Methoxybenzoyl)piperidin-1-yl)butyl]-7-methyl-6,7-dihydropyrrolo[2,3-c]azepine-4,8(1 H,5H)-dione
- 1-[4-(3-Benzoylpyrrolidin-1-yl)butyl]-7-methyl-6,7-dihydropyrrolo[2,3-c]azepine-4,8(1 H,5H)-dione
- 7-Benzyl-1-[4-(4-phenylpiperidin-1-yl)butyl-6,7-dihydropyrrolo[2,3-c]azepine-4,8(1 H,5H)-dione
- Synthesis of 1-[4-[4-(4-fluorobenzoyl)piperidin-1-yl]butyl]-4-hydroxyimino-7-methyl-6,7-dihydropyrrolo[2,3-c]-azepine-8-(1 H,5H)-one (Compound No. 61)
- A suspension of 2.838 g (10 mmol) of Compound No. 38 obtained in Example 17, 4.874 g (20 mmol) of 4-(4-fluorobenzoyl)piperidine hydrochloride and 5.528 g (40 mmol) of potassium carbonate in 150 mi of DMF was stirred for 14 hours at 80° C. The reaction mixture was filtered, a solid matter was washed with chloroform, and the filtrate and the washing were combined together, followed by concentration under reduced pressure.
- The residue was added with 600 mt of a 2:1 (v/v) mixed solvent of ethyl acetate and benzene. The organic layer was washed with a half-saturated aqueous solution of potassium carbonate, water (three times) and saturated saline, and was then dried over anhydrous sodium sulfate.
- The solvent was distilled off under reduced pressure and the resultant brown oil was purified by chromatography on a silica gel column (eluent: 10% methanol-chloroform), whereby 3.28 g of the title compound was obtained as a colorless oil. When treated in isopropyl ether, the oil was crystallized (yield: 72%).
- Although the compound is sufficiently pure, it can be recrystallized from isopropanol if necessary. Appearance: Colorless needle crystals. Melting point: 166-168 C.
- Synthesis of 1-[4-[4-(4-fluorobenzoyl)piperidin-1-yl]butyl]-4-hydroxyimino-7-methyl-6,7-dihydropyrrolo[2,3-c]-azepine-8(1 H,5H)-one p-toluenesulfonate (Compound No. 62)
- A mixture of 5.0 g (11.0 mmol) of Compound 61 obtained in Example 24 and 2.1 g (11.0 mmol) of p-toluenesulfonic acid monohydrate was heated in 120 mi of ethanol, so that the latter compounds were dissolved. The resultant mixture was allowed to cool down, whereby 6.5 g of the title compound were obtained as colorless crystals (yield: 92%).
- Appearance: Colorless needle crystals.
- Melting point: 197-198 C.
- Compound Nos. 58, 59 and 63 were obtained by using Compound Nos. 28, 37 and 29 in place of Compound No. 38 in the procedure described in Example 24.
- Compound No. 73 was also obtained by using 4-(4-chlorobenzoyl)piperidine hydrochloride in place of 4-(4-fluorobenzoyl)piperidine hydrochloride.
- Further, Compound No. 66 was obtained from Compound No. 47 and 4-(4-fluorobenzoyl)piperidine, and Compound Nos. 70 and 71 from Compound Nos. 24 and 41 and 4-benzoylpiperidine, respectively.
- 1-[3-[4-(4-Fluorobenzoyl)piperidin-1-yl]propyl]-7-methyl-6,7-dihydropyrrolo[2,3-c]azepine-4,8(1 H,5N)-dione
- 1-[3-[4-(4-Fluorobenzoy I)piperidi n-1-y I]propy I]-4-hydroxyim i no-7-methy I-6,7-di hydropyrro l0[2, 3-c]azepine-8-(1 H,5H)-one
- 1-[5-[4-(4-Fluorobenzoyl)piperidin-1-yl]pentyl]-7-methyl-6,7-dihydropyrrolo[2,3-c]azepine-4,8(1 H,5H)-dione
- 1-[4-[4-(4-Chlorobenzoyl)piperidin-1-yl]butyl]-4-hydroxyimino-7-methyl-6,7-dihydropyrrolo[2,3-c]azepine-8-(1 H,5H)-one
- 7-Benzyl-1-[4-[4-(4-fluorobenzoyl)piperidin-1-yl]butyl]-4-hydroxyimino-6,7-dihydropyrrolo[2,3-c]azepine-8-(1 H,5H)-one
- 1-[4-(4-Benzoylpiperidin-1-yl)butyl]-7-methyl-6,7-dihydropyrrolo[2,3-c]azepine-4,8(1 H,5N)-dione
- 1-[4-(4-Benzoylpiperidin-1-yl)butyl]-4-hydroxyimino-7-methyl-6,7-dihydropyrrolo[2,3-c]azepine-8(1 H,5H)-one
- Synthesis of 1-[4-[4-(4-fluorophenylsulfonyl)piperidin-1-yl]butyl]-4-hydroxyimino-7-methyl-6,7-dihydropyrrolo-[2,3-c]azepine-8(1 H,5H)-one (Compound No. 87)
- A suspension of 150 mg (0.53 mmol) of Compound No. 38 obtained by the procedure of Example 17, 177 mg (0.63 mmol) of 4-(4-fluorophenylsulfonyl)piperidine hydrochloride, 0.22 mt (1.59 mmol) of triethylamine and 149 mg (1.06 mmol) of sodium iodide in 3 m of DMF was heated for 25 hours at 80 C under stirring.
- The reaction mixture was then post-treated and purified as in Example 24, whereby 230 mg of the title compound were obtained as colorless crystals (yield: 89%). Although the compound is sufficiently pure, it can be recrystallized from methanol-ethanol if necessary.
- Appearance: Colorless needle crystals.
- Melting point: 190-192 C.
- Following the procedure described in Example 27, the following compounds were prepared from the corresponding various combinations of starting materials.
- Compound Nos. 85 and 86 were obtained from Compound No. 38 and 4-[(4-fluorophenyl)thio]piperidine hydrochloride and 4-[(4-fluorophenyl)sulfinyl]piperidine hydrochloride, respectively.
- Further, Compound Nos. 80, 94 and 88 were obtained from 4-(4-fluorobenzoyl)piperidine hydrochloride and Compound Nos. 39, 31 and 33, respectively.
- 1-[4-[4-[(4-Fluorophenyl)thio]piperidin-1-yl]butyl]-4-hydroxyimino-7-methyl-6,7-dihydropyrrolo[2,3-c]azepine-8(1 H,SN)-one
- 1-[4-[4-[(4-Fluorophenyl)sulfinyl]piperidin-1-yl]butyl]-4-hydroxyimino-7-methyl-6,7-dihydropyrrolo[2,3-c]-azepine-8(1 H,5H)-one
- 1-[4-[4-[(4-Fluorobenzoyl)piperidin-1-yl]butyl]-4-methoxyimino-7-methyl-6,7-dihydropyrrolo[2,3-c]azepine-8-(1 H,5H)-one
- 1-[4-[4-[(4-Fluorobenzoyl)piperidin-1-yl]butyl]-7-propyl-6,7-dihydropyrrolo[2,3-c]azepine-4,8(1 H,SH)-dione
- 7-Butyl-1-[4-[4-(4-fluorobenzoyl)piperidin-1-yl]butyl]-6,7-dihydropyrrolo[2,3-c]azepine-4,8(1 H,5H)-dione
- Synthesis of 7-ethyl-1-[4-[4-(4-fluorobenzoyl)piperidin-1-yl]butyl]-4-hydroxyimino-6,7-dihydropyrrolo[2,3-c]-azepine-8-(1 H,5N)-one (Compound No. 65)
- A suspension of 5.062 g (17 mmol) of Compound No. 43, 4.228 g (20.4 mmol) of 4-(4-fluorobenzoyl)-piperidine, 3.440 g (34 mmol) of triethylamine and 5.069 g (34 mmol) of sodium iodide in 200 m of DMF stirred for 20 hours at 80 C.
- The reaction mixture was then post-treated and purified as in Example 24. Recrystallization from ethanol gave 5.47 g of the title compound (yield: 69%). Appearance: Colorless needle crystals. Melting point: 158-160 °C.
- Following the procedure described in Example 29, the following compounds were prepared from the corresponding various combinations of starting materials.
- Compound Nos. 74, 75, 76, 81, 82, 83 and 89 were obtained from 4-(4-fluorobenzoyl)piperidine and Compound Nos. 36, 44, 45, 22, 30, 34 and 46, respectively.
- Further, Compound Nos. 77 and 84 were obtained from Compound No. 38 and 3-(4-fluorobenzoyl)-piperidine and 4-(4-fluorophenoxy)piperidine, respectively.
- 1-[4-[4-(4-Fluorobenzoyl)piperidin-1-yl]butyl]-4-hydroxyimino-6,7-dihydropyrrolo[2,3-c]azepine-8(1 H,5H)-one
- 1-[4-[4-(4-Fluorobenzoyl)pi peridi n-1-yl]butyl]-4-hydroxyimino-7-propyl-6,7-di hydropyrrolo[2,3-c]azepine-8-(1 H,5H)-one
- 1-[4-[4-(4-Fluorobenzoyl)piperidin-1-yl]butyl]-4-hydroxyimino-7-isopropyl-6,7-dihydropyrrolo[2,3-c]azepine-8-(1H,5H)-one
- 1-[4-[4-(4-Fluorobenzoyl)piperidin-1-yl]butyl]-6,7-dihydropyrrolo[2,3-c]azepine-4,8(1 H,5H)-dione
- 7-Ethyl-1-[4-[4-(4-fluorobenzoyl)piperidin-1-yl]butyl]-6,7-dihydropyrrolo[2,3-c]azepine-4,8(1 H,5H)-dione
- 7-Benzyl-1-[4-[4-(4-fluorobenzoyl)piperidin-1-yl]butyl]-6,7-dihydropyrrolo[2,3-c]azepine-4,8(1 H,5H)-dione
- 7-Butyl-1-[4-[4-(4-fluorobenzoyl)piperidin-1-yl]butyl]-4-hydroxyimino-6,7-dihydropyrrolo[2,3-c]azepine-8-(1 H,5H)-one
- 1-[4-[3-(4-Fluorobenzoyl)piperidin-1-yl]butyl]-4-hydroxyi m i no-7-methyl-6,7-d i hydropyrrolo[2,3-c]azepine-8-(1 H,5H)-one
- 1-[4-[4-(4-Fluorophenoxy)piperidin-1-yl]butyl]-4-hydroxyimino-7-methyl-6,7-dihydropyrrolo[2,3-c]azepine-8-(1 H,5H)-one
- Synthesis of 4-benzyloxyimino-1-[4-[4-(4-fluorobenzoyl)piperidin-1-yl]butyl]-7-methyl-6,7-dihydropyrrolo[2,3-c]azepine-8-(1 H,5H)-one (Compound No. 90)
- A suspension of 7.48 g (20 mmol) of Compound No. 40 obtained in Example 21, 5.85 g (24 mmol) of 4-(4-fluorobenzoyl)piperidine hydrochloride, 6.48 g (64 mmol) of triethylamine and 6.00 g (40 mmol) of sodium iodide in 300 m of acetonitrile was refluxed for 24 hours. The reaction mixture was concentrated under reduced pressure. The residue was added with 300 m of a half-saturated aqueous solution of potassium carbonate and then extracted with dichloromethane (300 m x twice).
- The dichloromethane layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the resulting brown oil was purified by chromatography on a silica gel column (eluent: 5% methanol-chloroform), whereby 8.51 g of the title compound were obtained (yield: 78%). Appearance: Yellow oil.
- Synthesis of 1-[4-[4-[2-(4-fluorophenyl)-1,3-dioxolanyl]]piperidin-1-yl]butyl]-4-hydroxyimino-7-methyl-6,7-dihydropyrrolo[2,3-c]azepine-8-(1 H,5H)-one (Compound No. 93)
- A suspension of 2.838 g (10 mmol) of Compound No. 38 obtained in Example 17, 3.016 g (12 mmol) of 4-(4-fluorobenzoyl)piperidine ethyleneacetal, 2.024 g (20 mmol) of triethylamine and 2.998 g (20 mmol) of sodium iodide in 500 m ℓ of acetonitrile was refluxed for 24 hours.
- The reaction mixture was concentrated under reduced pressure. The residue was added with 300 m of chloroform, washed with water and saturated saline, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the resulting yellow oil was purified by chromatography on a silica gel column (eluent: 10% methanol-chloroform), whereby 4.375 g of the title compound were obtained as a solid yellow solid (yield: 88%).
- Although the compound is sufficiently pure, it can be recrystallized from isopropyl alcohol-isopropyl ether if necessary.
- Appearance: Colorless prism crystals.
- Melting point: 149.0-150.5 C.
- Synthesis of 1-[4-(4-cyano-4-phenylpiperidin-1-yl)butyl]-7-methyl-6,7-dihydropyrrolo[2,3-c]azepine-4,8-(1 H,5H)-dione (Compound No. 56)
- The title compound was obtained from Compound No. 23 obtained in Example 14 and 4-cyano-4-phenylpiperidine hydrochloride in accordance with the procedure of Example 29 except that triethylamine was replaced by the same mole number of potassium carbonate. Example 34
- Following the procedure described in Example 33, Compound Nos. 57 and 79 were obtained from the combinations of Compound No. 38 and 4-cyano-4-phenylpiperidine hydrochloride and 3-(4-fluorobenzoyl)-pyrrolidine hydrochloride.
- Further, Compound No. 64 was also obtained from the combination of Compound No. 42 and 4-(4-fluorobenzoyl)piperidine hydrochloride.
- 1-[4-(4-Cyano-4-phenylpiperidin-1-yl)butyl]-4-hydroxyimino-7-methyl-6,7-dihydropyrrolo[2,3-c]azepine-8-(1 H,5H)-one
- 1-[4-[3-(4-fluorobenzoyl)pyrrolidin-1-yl)butyl]-4-hydroxyimino-7-methyl-6,7-dihydropyrrolo[2,3-c]azepine-8-(1 H,5H)-one
- 1-[5-[4-(4-Fluorobenzoyl)piperidin-1-yl]pentyl]-4-hydroxyimino-7-methyl-6,7-dihydropyrrolo[2,3-c]azepine-8-(1 H,5H)-one
- Synthesis of 7-methyl-1-[4-(4-phenylpiperidin-1-yl)butyl]-6,7-dihydropyrrolo[2,3-c]azepine-4,8(1H,5H)-dione (Compound No. 49)
- A suspension of 806 mg (3 mmol) of Compound No. 23 obtained in Example 14, 1.935 g (12 mmol) of 4-phenylpiperidine and 4.500 g (30 mmol) of sodium iodide in 70 m of DMF was stirred for 5 hours at 80 C. The reaction mixture was allowed to cool down, followed by the addition of 500 m ℓ of a 2:1 (v/v) mixed solvent of ethyl acetate and benzene. The organic layer was washed with a half-saturated aqueous solution of potassium carbonate, water (three times) and saturated saline, and was then dried over anhydrous sodium sulfate.
- The solvent was distilled off under reduced pressure and the resultant oil was purified by chromatography on a silica gel column (eluent: 5% methanolchloroform), whereby 1.106 g of the title compound were obtained as a pale yellow oil (yield: 94%).
- The title compound which was in the free form was converted to its hydrochloride (Compound No. 50) by a method known per se in the art. The hydrochloride was recrystallized from isopropanol-isopropyl ether. Appearance: Pale yellow plate crystals.
- Melting point: 208-210°C.
- Synthesis of 4-hydroxyimino-7-methyl-1-[4-(4-phenylpiperidin-1-yl)butyl]-6,7-dihydropyrrolo[2,3-c]azepine-8-(1H,5H)-one (Compound No. 51)
- A solution of 590 mg (1.5 mmol) of the free compound (Compound No. 49) obtained in Example 35 and 521 mg (7.5 mmol) of hydroxylamine hydrochloride in 40 mℓ of pyridine was stirred for 16 hours at room temperature.
- After the reaction mixture was concentrated under reduced pressure, toluene was added. The resultant mixture was concentrated again under reduced pressure. The residue was added with 300 m of a half-saturated aqueous solution of potassium carbonate and then extracted with chloroform. The extract was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The resultant oil was purified by chromatography on a silica gel column (eluent: 10% methanolchloroform), whereby 546 mg of a colorless oil was obtained. The oil was treated in isopropyl ether so that it was crystallized. Although the compound is sufficiently pure, it can be recrystallized from isopropanol-ether if necessary.
- Appearance: Colorless prism crystals.
- Melting point: 164-165 C.
- Synthesis of 4-acetoxyimino-1-[4-[4-(4-fluorobenzoyl)piperidin-1-yl)butyl]-7-methyl-6,7-dihydropyrrolo[2,3-c]-azepine-8(1 H,5H)-one (Compound No. 91)
- To a solution of 5.00 g (11.0 mmol) of Compound No. 61, which had been obtained in Example 24, in 50 mℓ of pyridine, 1.56 mℓ (22.0 mmol) of acetyl chloride were added. The resulting mixture was stirred for 3 hours at room temperature.
- After the reaction mixture was concentrated under reduced pressure, 100 m of water was added, followed by the extraction with 400 mℓ of dichloromethane. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off and the resultant brown oil was purified by chromatography on a silica gel column (eluent: 3% methanol-chloroform), whereby 4.30 g of the title compound were obtained as a colorless oil (yield: 79%).
- Appearance: Colorless oil.
- Synthesis of 4-benzoyloxyimino-1-[4-[4-(4-fluorobenzoylpiperidin)-1-yl]butyl]-7-methyl-6,7-dihydropyrrolo-[2,3-c]azepine-8(1 H,5H)-one (Compound No. 92)
- To a solution of 227 mg (0.5 mmol) of Compound No. 61, which had been obtained in Example 24, and 92 mg (0.75 mmol) of benzoic acid in 10 mℓ of DMF, a solution of 122 mg (0.75 mmol) of diethyl cyanophosphonate in 5 mℓ of DMF and another solution of 152 mg (1.5 mmol) of triethylamine in 5 mℓ of DMF were added successively and gradually, and the resultant mixture was stirred for 16 hours at room temperature. The reaction mixture was added with 300 mt of a 3:1 (v/v) mixture of ethyl acetate and benzene, washed with a saturated aqueous solution of potassium carbonate, water (three times) and saturated saline, and then dried over anhydrous sodium sulfate.
- The solvent was distilled off under reduced pressure and the resultant brown oil was purified by chromatography on a silica gel column (eluent: 5% methanol-chloroform), whereby 252 mg of the title compound were obtained (yield: 90%). Appearance: Yellow oil.
- Synthesis of 4-benzoyloxyimino-1-[4-[4-(4-fluorobenzoylpiperidin)-1-yl]butyl]-7-methyl-6,7-dihydropyrrolo-[2,3-c]azepine-8(1 H,5H)-one (Compound No. 92) (Alternative process):
- To a solution of 227 mg (0.5 mmol) of Compound 61, which had been obtained in Example 24, in 10 m of pyridine, 1 mℓ of benzoyl chloride was slowly added dropwise under ice cooling and stirring. After the resultant mixture was stirred for 16 hours at room temperature, the reaction mixture was concentrated under reduced pressure. The residue was added with 300 mt of ethyl acetate. The organic layer was washed with a saturated aqueous solution of potassium carbonate (twice), water (twice) and saturated saline, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the resulting brown oil was purified by chromatography on a silica gel column (eluent: 5% methanol- chloroform), whereby 240 mg of the title compound were obtained (yield: 86%).
- Synthesis of 1-[4-[4-(4-fiuorobenzoyi)piperidin-1 -yl]butyl]-7-methyl-6,7-dihydropyrro!o[2,3-c]azepine-4,8-(1 H,5H)-dione benzylbromide (Compound No. 95)
- Dissolved in 1 m of acetone were 31.5 mg (0.072 mmol) of Compound No. 60 obtained in Example 22, followed by the addition of 1.5 mℓ of benzyl bromide. The resultant mixture was stirred for 21 hours at room temperature. Benzene and n-hexane were added in suitable amounts, followed by trituration. Crude crystals thus obtained were collected by filtration and washed with n-hexane (yield: 36 mg, 82%). They were recrystallized from acetone, whereby the title compound was obtained as colorless crystals.
- Melting point: 150-155 C.
- Compound Nos. 96 and 97 were obtained by changing benzyl bromide to methyl iodide and ethyl bromide, respectively in Example 40.
- 1-[4-[4-(4-Fluorobenzoyl)piperidin-1-yl]butyl]-7-methyl-6,7-dihydropyrrolo[2,3-c]azepine-4,8(1 H,5H)-dione methyliodide.
- 1-[4-[4-(4-Fluorobenzoyl)piperidin-1-yl]butyl]-7-methyl-6,7-dihydropyrrolo[2,3-c]azepine-4,8(1 H,5H)-dione ethylbromide.
- Synthesis of 4-benzoyloxyimino-1-(4-chlorobutyl)-7-methyl-6,7-dihydropyrrolo[2,3-c]azepine-8(1H,SH)-one (Compound No. 98)
- A solution of 4.256 g (15 mmol) of Compound No. 38, which had been obtained in Example 17, and 2.748 g (22.5 mmol) of benzoic acid in 60 m ℓ of DMF was cooled to 0°C, to which a solution of 3.670 g (22.5 mmol) of diethyl cyanophosphate in 20 m of DMF and another solution of 2.277 g (22.5 mmol) of triethylamine in 20 m ℓ of DMF were successively and gradually added. The resultant mixture was stirred for 1 hour at the same temperature and for additional 4 hours at room temperature.
- The reaction mixture was concentrated under reduced pressure and 600 m of a 3:1 (v/v) mixed solvent of ethyl acetate and benzene were added to the residue. The organic layer was washed with a 10% aqueous solution of citric acid, water (three times) and saturated saline and was then dried over anhydrous sodium sulfate. The solvent was thereafter distilled off under reduced pressure. The resulting brown oil was purified by chromatography on a silica gel column (eluent: 1:1 mixed solvent of ethyl acetate and hexane) and then recrystallized from isopropyl ether, whereby 5.604 g of the title compound were obtained (yield: 87%)
- Appearance: Colorless prism crystals.
- Melting point: 123.5-125.0 C.
- Synthesis of 4-benzoyloxyimino-1-[4-[4-(4-fluorobenzoyl)piperidine-1-yl]butyl]-7-methyl-6,7-dihydropyrrolo-[2,3-c]azepine-8(1 H,5H)-one (Compound No.92)
- A suspension of 3.879 g (10 mmol) of Compound No. 98 obtained in Example 42, 2.437 g (10 mmol) of 4-(4-fluorobenzoyl)piperidine hydrochloride, 3.000 g (20 mmol) of sodium iodide and 3.036 g (30 mmol) of triethylamine in 50 m of CH3CN was refluxed for 20 hours.
- The reaction mixture was concentrated under reduced pressure. The residue was added with 300 m ℓ of a half-saturated aqueous solution of potassium carbonate, followed by the extraction with dichloromethane (200 mℓ x 3 times). The dichloromethane layers were combined, washed with 200 m of saturated saline, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure.
- The resulting brown oil was purified by chromatography on a silica gel column (eluent: 10% methanol- chloroform), whereby 2.953 g of the title compound were obtained (yield: 53%).
-
- Test
- With respect to the compounds of the present invention, their anti-α1 action and anti-serotonin action were investigated by the testing methods which will be described below. The test results of some representative compounds are summarized in Table 2.
- The thoracic aorta of each Hartley male guinea pig (body weight: 300-500 g) was excised. The sample cut in a helical form was suspended under 1 g load in a Magnus cylinder filled with the Tyrode solution of 37° C which had been saturated with a mixed gas consisting of 95% CO2 + 5% Oz. Using an isometric transducer (TB-612J/NIHON KOHDEN) and a pressure preamplifier (AP-620G/NIHON KOHDEN), variations in tension were measured. The measurement results were recorded on a thermal pen-writing recorder (WT-647G/NIHON KOHDEN). Taking the tonic contraction induced by 10-5 M norepinephrine (NE) as 100%, the percent contractions upon addition of each test drug at 10-8 and 10-7 M were determined as anti-α1 action.
- The superior mesenteric artery of each Hartley male guinea pig (body weight: 300-500 g) was excised. The sample cut in a helical form was suspended under 0.3 g load in a Magnus cylinder filled with the Tyrode solution of 37 C which had been saturated with a mixed gas consisting of 95% CO2 + 5% Oz. Using an isometric transducer (UL-10/SHINKOH K.K.) and a pressure preamplifier (DSA-605A/SHINKOH K.K.), variations in tension were measured. The measurement results were recorded on a pen-writing recorder (VP-6537A/NATIONAL K.K.). Taking the phosic contraction induced by 10-5 M serotonin as 100%, the percent contractions in the presence of each test drug at 10-7 and 10-6 M were determined as anti-5-NT action.
Claims (14)
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP26137/90 | 1990-02-07 | ||
JP2613790 | 1990-02-07 | ||
JP02773991A JP3198117B2 (en) | 1990-02-07 | 1991-01-30 | Pyrroloazepine derivatives |
JP27739/91 | 1991-01-30 |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0441349A1 true EP0441349A1 (en) | 1991-08-14 |
EP0441349B1 EP0441349B1 (en) | 1996-01-03 |
Family
ID=26363881
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP91101616A Expired - Lifetime EP0441349B1 (en) | 1990-02-07 | 1991-02-06 | Pyrroloazepine derivatives |
Country Status (10)
Country | Link |
---|---|
US (3) | US5206239A (en) |
EP (1) | EP0441349B1 (en) |
JP (1) | JP3198117B2 (en) |
KR (1) | KR100255131B1 (en) |
AT (1) | ATE132497T1 (en) |
AU (1) | AU642960B2 (en) |
CA (1) | CA2035749C (en) |
DE (1) | DE69115943T2 (en) |
DK (1) | DK0441349T3 (en) |
ES (1) | ES2084719T3 (en) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0551527A1 (en) * | 1991-08-07 | 1993-07-21 | Suntory Limited | Pyrroloazepine derivative |
EP0557526A1 (en) * | 1991-08-07 | 1993-09-01 | Suntory Limited | Pyrroloazepine compound |
FR2723091A1 (en) * | 1994-07-29 | 1996-02-02 | Esteve Labor Dr | TETRAHYDROPYRIDINE- (6,4-HYDROXYPIPERIDINE) ALKYLAZOLES |
EP0807632A1 (en) * | 1995-12-01 | 1997-11-19 | Suntory Limited | Pyrroloazepine derivatives |
WO1998041527A1 (en) * | 1997-03-14 | 1998-09-24 | Suntory Limited | Pyrroloazepine compounds |
US6355659B1 (en) | 1994-07-29 | 2002-03-12 | Laboratorios Del Dr. Esteve, S.A. | 4-(4-Chlorophenyl)-1236-tetrahydro-1(1H-124-triazol-1-yl)butty)pyrideine and salts thereof; pharmaceutical compositions and method of treating psychoses utilizing same |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP3198117B2 (en) * | 1990-02-07 | 2001-08-13 | サントリー株式会社 | Pyrroloazepine derivatives |
JP3714685B2 (en) * | 1994-05-18 | 2005-11-09 | 第一サントリーファーマ株式会社 | Hymenialdisine and its derivatives, methods for producing their synthetic intermediates, and synthetic intermediates thereof |
JPH11193290A (en) | 1997-12-26 | 1999-07-21 | Suntory Ltd | Pyrrole sulfonamide-based compound |
JPH11193289A (en) | 1997-12-26 | 1999-07-21 | Suntory Ltd | Pyrrole sulfonamide derivative |
JP4953826B2 (en) | 2007-01-05 | 2012-06-13 | ソニー株式会社 | Information processing apparatus, display control method, and program |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1987007274A2 (en) * | 1986-05-29 | 1987-12-03 | Harbor Branch Oceanographic Institution, Inc. | Antitumor compositions and their methods of use |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3563979A (en) * | 1966-10-21 | 1971-02-16 | Upjohn Co | 1,2,3,4,5,6 - hexahydroazepino(4,3 - b)indoles and 1,2,3,4,5,6-hexahydroazepino(3,2-b)indoles |
US3573324A (en) * | 1969-02-28 | 1971-03-30 | Upjohn Co | 2,3,4,5,10,10a-hexahydroazepino(2,3-b)indoles |
US3573323A (en) * | 1969-02-28 | 1971-03-30 | Upjohn Co | 1,2,3,4,5,10-hexahydroazepino(2,3-b)indoles |
JPS62161786A (en) * | 1986-01-08 | 1987-07-17 | Mitsubishi Chem Ind Ltd | Pyrrole compound |
DE3903368A1 (en) * | 1989-02-04 | 1990-08-09 | Basf Ag | METHOD FOR PRODUCING CONDENSED CYCLIC AMIDINES |
JP3198117B2 (en) * | 1990-02-07 | 2001-08-13 | サントリー株式会社 | Pyrroloazepine derivatives |
-
1991
- 1991-01-30 JP JP02773991A patent/JP3198117B2/en not_active Expired - Fee Related
- 1991-02-06 EP EP91101616A patent/EP0441349B1/en not_active Expired - Lifetime
- 1991-02-06 AU AU70806/91A patent/AU642960B2/en not_active Ceased
- 1991-02-06 AT AT91101616T patent/ATE132497T1/en not_active IP Right Cessation
- 1991-02-06 CA CA002035749A patent/CA2035749C/en not_active Expired - Fee Related
- 1991-02-06 DK DK91101616.0T patent/DK0441349T3/en active
- 1991-02-06 ES ES91101616T patent/ES2084719T3/en not_active Expired - Lifetime
- 1991-02-06 DE DE69115943T patent/DE69115943T2/en not_active Expired - Fee Related
- 1991-02-07 US US07/651,778 patent/US5206239A/en not_active Expired - Lifetime
-
1992
- 1992-12-09 US US07/987,703 patent/US5391731A/en not_active Expired - Fee Related
-
1994
- 1994-02-14 US US08/195,019 patent/US5416082A/en not_active Expired - Fee Related
-
1999
- 1999-05-20 KR KR1019990018369A patent/KR100255131B1/en not_active IP Right Cessation
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1987007274A2 (en) * | 1986-05-29 | 1987-12-03 | Harbor Branch Oceanographic Institution, Inc. | Antitumor compositions and their methods of use |
Non-Patent Citations (2)
Title |
---|
Journal of the Chemical Society Chemical Communications, 1980, C.M. SHARMA et al.: "Characterization of a Yellow Compound Isolated from the Marine Sponge Phakellia flabellata", pages 435-436. * |
Tetrahedron, Vol. 41, No. 24, 1985, G. DE NANTEUIL et al.: "Invertebres marins du lagon neo-caledonien. V. Isolement et identification des metabolites d'une nouvelle espece de spongiaire, pseudaxinyssa cantharella", pages 6019-6033. * |
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0551527A1 (en) * | 1991-08-07 | 1993-07-21 | Suntory Limited | Pyrroloazepine derivative |
EP0557526A1 (en) * | 1991-08-07 | 1993-09-01 | Suntory Limited | Pyrroloazepine compound |
EP0551527A4 (en) * | 1991-08-07 | 1994-08-31 | Suntory Limited | |
EP0557526A4 (en) * | 1991-08-07 | 1994-08-31 | Suntory Limited | |
FR2723091A1 (en) * | 1994-07-29 | 1996-02-02 | Esteve Labor Dr | TETRAHYDROPYRIDINE- (6,4-HYDROXYPIPERIDINE) ALKYLAZOLES |
WO1996004287A1 (en) * | 1994-07-29 | 1996-02-15 | Laboratorios Del Dr. Esteve, S.A. | Tetrahydropyridine-(or 4-hydroxypiperidine)alkylazoles having an affinity for sigma and/or 5ht1a receptors |
US5731331A (en) * | 1994-07-29 | 1998-03-24 | Laboratorios Del Dr. Esteve, S.A. | Tetrahydropyridine-(or 4-hydroxypiperidine) alkylazoles |
US6355659B1 (en) | 1994-07-29 | 2002-03-12 | Laboratorios Del Dr. Esteve, S.A. | 4-(4-Chlorophenyl)-1236-tetrahydro-1(1H-124-triazol-1-yl)butty)pyrideine and salts thereof; pharmaceutical compositions and method of treating psychoses utilizing same |
EP0807632A1 (en) * | 1995-12-01 | 1997-11-19 | Suntory Limited | Pyrroloazepine derivatives |
EP0807632A4 (en) * | 1995-12-01 | 1998-12-09 | Suntory Ltd | Pyrroloazepine derivatives |
US5962448A (en) * | 1995-12-01 | 1999-10-05 | Suntory Limited | Pyrroloazepine derivatives |
WO1998041527A1 (en) * | 1997-03-14 | 1998-09-24 | Suntory Limited | Pyrroloazepine compounds |
Also Published As
Publication number | Publication date |
---|---|
CA2035749C (en) | 2001-10-23 |
US5416082A (en) | 1995-05-16 |
JP3198117B2 (en) | 2001-08-13 |
ATE132497T1 (en) | 1996-01-15 |
AU642960B2 (en) | 1993-11-04 |
DE69115943T2 (en) | 1996-11-14 |
ES2084719T3 (en) | 1996-05-16 |
US5391731A (en) | 1995-02-21 |
US5206239A (en) | 1993-04-27 |
DK0441349T3 (en) | 1996-05-13 |
CA2035749A1 (en) | 1991-08-08 |
AU7080691A (en) | 1991-08-08 |
KR100255131B1 (en) | 2000-04-15 |
JPH0597856A (en) | 1993-04-20 |
DE69115943D1 (en) | 1996-02-15 |
EP0441349B1 (en) | 1996-01-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP0441349B1 (en) | Pyrroloazepine derivatives | |
EP0557526B1 (en) | Pyrroloazepine compound | |
US4640922A (en) | 3N-substituted 3,4-dihydropyrimidines as agents for treating disorders of cardiovascular system | |
US6624314B2 (en) | Pyrrolothiazine and pyrrolothiazepine compounds having serotonin-2 receptor antagonistic and alpha-1-blocking action | |
US6294677B1 (en) | Thiopyran derivatives | |
EP0551527B1 (en) | Pyrroloazepine derivative | |
US6743913B2 (en) | Pyrrolothiazine and pyrrolothiazepine compounds having serotonin-2 receptor antagonistic and α-1-blocking action | |
US6211362B1 (en) | Pyrroloazepine compounds | |
KR100229403B1 (en) | Pyrroloazepine derivatives |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FR GB GR IT LI LU NL SE |
|
17P | Request for examination filed |
Effective date: 19920116 |
|
17Q | First examination report despatched |
Effective date: 19931201 |
|
GRAA | (expected) grant |
Free format text: ORIGINAL CODE: 0009210 |
|
AK | Designated contracting states |
Kind code of ref document: B1 Designated state(s): AT BE CH DE DK ES FR GB GR IT LI LU NL SE |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: GR Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 19960103 |
|
REF | Corresponds to: |
Ref document number: 132497 Country of ref document: AT Date of ref document: 19960115 Kind code of ref document: T |
|
REF | Corresponds to: |
Ref document number: 69115943 Country of ref document: DE Date of ref document: 19960215 |
|
ITF | It: translation for a ep patent filed |
Owner name: ING. A. GIAMBROCONO & C. S.R.L. |
|
ET | Fr: translation filed | ||
REG | Reference to a national code |
Ref country code: CH Ref legal event code: NV Representative=s name: A. BRAUN, BRAUN, HERITIER, ESCHMANN AG PATENTANWAE |
|
REG | Reference to a national code |
Ref country code: DK Ref legal event code: T3 |
|
REG | Reference to a national code |
Ref country code: ES Ref legal event code: FG2A Ref document number: 2084719 Country of ref document: ES Kind code of ref document: T3 |
|
PLBE | No opposition filed within time limit |
Free format text: ORIGINAL CODE: 0009261 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT |
|
26N | No opposition filed | ||
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: SE Payment date: 20010206 Year of fee payment: 11 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: LU Payment date: 20010213 Year of fee payment: 11 Ref country code: DK Payment date: 20010213 Year of fee payment: 11 Ref country code: AT Payment date: 20010213 Year of fee payment: 11 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: NL Payment date: 20010228 Year of fee payment: 11 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: BE Payment date: 20010427 Year of fee payment: 11 |
|
REG | Reference to a national code |
Ref country code: GB Ref legal event code: IF02 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: LU Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20020206 Ref country code: AT Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20020206 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: SE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20020207 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: DK Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20020228 Ref country code: BE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20020228 |
|
BERE | Be: lapsed |
Owner name: SUNTORY LTD Effective date: 20020228 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: NL Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20020901 |
|
EUG | Se: european patent has lapsed |
Ref document number: 91101616.0 |
|
REG | Reference to a national code |
Ref country code: DK Ref legal event code: EBP |
|
NLV4 | Nl: lapsed or anulled due to non-payment of the annual fee |
Effective date: 20020901 |
|
REG | Reference to a national code |
Ref country code: GB Ref legal event code: 732E |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: PUE Owner name: DAIICHI SUNTORY PHARMA CO., LTD. Free format text: SUNTORY LIMITED#1-40, DOJIMAHAMA 2-CHOME#KITA-KU, OSAKA-SHI, OSAKA 530 (JP) -TRANSFER TO- DAIICHI SUNTORY PHARMA CO., LTD.#7-2, KOJIMACHI 5-CHOME#CHIYODA-KU, TOKYO (JP) Ref country code: CH Ref legal event code: NV Representative=s name: ARNOLD & SIEDSMA AG |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: TP |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: GB Payment date: 20050202 Year of fee payment: 15 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: DE Payment date: 20050203 Year of fee payment: 15 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: FR Payment date: 20050208 Year of fee payment: 15 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: CH Payment date: 20050216 Year of fee payment: 15 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: ES Payment date: 20050323 Year of fee payment: 15 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: GB Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20060206 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: ES Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20060207 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: LI Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20060228 Ref country code: CH Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20060228 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: IT Payment date: 20060228 Year of fee payment: 16 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: DE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20060901 |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: PL |
|
GBPC | Gb: european patent ceased through non-payment of renewal fee |
Effective date: 20060206 |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: ST Effective date: 20061031 |
|
REG | Reference to a national code |
Ref country code: ES Ref legal event code: FD2A Effective date: 20060207 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: FR Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20060228 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: IT Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20070206 |